文章基本信息

标题：In silico derived small molecules targeting the finger-finger interaction between the histone lysine methyltransferase NSD1 and Nizp1 repressor
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作者：Andrea Berardi ; Michela Ghitti ; Giacomo Quilici 等
期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2020
卷号：18
页码：4082-4092
DOI：10.1016/j.csbj.2020.11.044
出版社：Computational and Structural Biotechnology Journal
摘要：PHD fingers are small chromatin binding domains, that alone or in tandem work as versatile interaction platforms for diversified activities, ranging from the decoding of the modification status of histone tails to the specific recognition of non-histone proteins. They play a crucial role in their host protein as mutations thereof cause several human malignancies. Thus, PHD fingers are starting to be considered as valuable pharmacological targets. While inhibitors or chemical probes of the histone binding activity of PHD fingers are emerging, their druggability as non-histone interaction platform is still unexplored. In the current study, using a computational and experimental pipeline, we provide proof of concept that the tandem PHD finger of Nuclear receptor-binding SET (Su(var)3–9, Enhancer of zeste, Trithorax) domain protein 1 (PHD V C5HCH NSD1 ) is ligandable. Combining virtual screening of a small subset of the ZINC database (Zinc Drug Database, ZDD, 2924 molecules) to NMR binding assays and ITC measurements, we have identified Mitoxantrone dihydrochloride, Quinacrine dihydrochloride and Chloroquine diphosphate as the first molecules able to bind to PHD V C5HCH NSD1 and to reduce its documented interaction with the Zinc finger domain (C2HR Nizp1 ) of the transcriptional repressor Nizp1 (NSD1-interacting Zn-finger protein). These results pave the way for the design of small molecules with improved effectiveness in inhibiting this finger-finger interaction.
关键词：PHD finger ; NSD1 ; Nizp1 ; Protein-protein interactions ; Virtual screening ; NMR